A patient with ipilimumab-refractory melanoma is shown before (left), after one cycle, and after three cycles of treatment with the anti–PD-1 antibody MK-3475 (10 mg/kg every 3 weeks).

New Approaches Revolutionize the Treatment of Advanced Melanoma

By Sarah Bronson

Recent breakthroughs in immunotherapy and targeted therapy have improved outcomes for patients with advanced melanoma.

For decades, the median survival time for patients with advanced
melanoma remained less than a year. But newly available treatments
portend a better outlook for patients with this cancer.

Researchers have developed immunotherapies designed to prevent melanoma
from deactivating T cells, targeted therapy combinations that block
oncogenic pathways in the tumor cells, and multimodality approaches
intended to both destroy the cancer and help prevent its recurrence.
Patrick Hwu, M.D., a professor in and chair of the Department of
Melanoma Medical Oncology at The University of Texas MD Anderson Cancer
Center, said, “It’s an exciting time. Ten years ago, we could cure
about 5% of patients with advanced melanoma, and now we can achieve
very good responses in 20%–25% of these patients because we have so
many possible tools. And I believe we can drive response rates even
higher and increase the durations of these responses over the next few
years.”

Immune checkpoint blockades

Melanoma and other cancers can subvert T cells’ self-limiting
mechanisms in multiple ways. Two signals are required for an effective
T cell response: an antigen on an antigen-presenting cell binds to a T
cell receptor on the T cell, and a molecule on the T cell called CD28
interacts with a molecule on the antigen-presenting cell called B7.
This double signal helps ensure that T cells attack antigens rather
than healthy tissue. As a measure to protect healthy cells and minimize
nonspecific T cell activation, a molecule expressed on the surface of
activated T cells called cytotoxic T lymphocyte antigen 4 (CTLA-4) can
halt T cell activation by conjugating with B7 in place of CD28. This
function, which can also deactivate T cells, is an important barrier to
antitumor immunotherapy.

To maintain T cell activation in response to cancer, researchers led by
James Allison, Ph.D., then a professor at the University of California,
Berkeley, and now a professor in and chair of the Department of
Immunology at MD Anderson, designed an antibody with a high affinity
for CTLA-4 called ipilimumab. When ipilimumab binds to CTLA-4, the
interaction between CD28 and B7 can continue, leading to T cell
activation and an antitumor immune response. This intervention was the
first of a new type of immunotherapy called immune checkpoint blockade.

In the phase III trial that led to the approval of ipilimumab in 2011
by the U.S. Food and Drug Administration (FDA), patients with
metastatic melanoma treated with 3 mg of ipilimumab per kilogram of
body weight every 3 weeks for up to four treatments had an overall
response rate of 10.9% after 55 months of follow-up, whereas those
treated with a melanoma peptide vaccine had an overall response rate of
1.5%. And in an expanded access program at MD Anderson in which
patients with advanced melanoma received induction therapy with 10
mg/kg of ipilimumab every 3 weeks for a total of four doses (and
eligible patients received continued maintenance therapy every 3
months), 14% of patients had complete responses and another 2% had
partial responses after induction therapy.

The initial response rates for ipilimumab were similar to those of the
previous standard treatments for advanced melanoma, dacarbazine or
interleukin-2 (IL-2); however, the responses to ipilimumab have been
much more durable. In MD Anderson’s experience treating advanced
melanoma with ipilimumab, patients whose disease responded to the drug
have had a 5-year overall survival rate of 80%. “With chemotherapy, the
tumor can grow back if some silent part of the cancer has been left
alive. With immunotherapy, complete remission may mean a cure because
the immune system is equipped to recognize any remainder of the
cancer,” said Wen-Jen Hwu, M.D., Ph.D., a professor in the Department
of Melanoma Medical Oncology.

The most common toxic effects of ipilimumab are colitis; a rash that
can cause severe skin peeling; and hypophysitis, which can cause
headaches, vision disturbances, and changes in various hormone levels.

Another crucial immune checkpoint is the pathway between programmed
cell death protein 1 (PD-1) and its ligand, PD-L1. Activated T cells
and B cells express surface PD-1, and antigen-presenting cells express
surface PD-L1. Interaction between PD-1 on T cells and PD-L1
deactivates the T cells. Many cancers, including 40% of melanomas,
disrupt T cells’ antitumor surveillance by expressing PD-L1 themselves.
The PD-1–PD-L1 interaction is an important mechanism leading to immune
tolerance to cancer, and blocking this interaction may restore
antitumor surveillance.

Computed tomography images show metastatic melanoma lesions (circled) in the small bowel and mesentery of an 83-year-old patient before (top) and after 6, 12, and 32 weeks of treatment with an anti–PD-L1 antibody. The patient remained in complete remission until his death from heart failure 2 years after treatment was discontinued.

To combat the suppression of T cells by cancer cells, researchers have
developed antibodies that target PD-1 and PD-L1. Dr. Wen-Jen Hwu is
currently leading a phase II trial in which patients with unresectable
or metastatic melanoma are treated with the anti–PD-1 antibody
nivolumab. And in an ongoing phase I trial led by Dr. Hwu, the
anti–PD-1 antibody MK-3475 is being used to treat advanced melanoma.
“Early data from both trials show response rates and response durations
that are unprecedented among immunotherapy agents to date,” she said.

A prominent difference between the PD-1 pathway blockers and ipilimumab
is the extent of their toxicity. “Anti–PD-1 and anti–PD-L1 are quieter
than ipilimumab—their toxic effects are less severe,” said Srisuda
Lecagoonporn, R.N., a research nurse in the Department of Melanoma
Medical Oncology. “From the patient’s perspective, anti–PD-1 and
anti–PD-L1 are a better experience.” The most common adverse effects of
PD-1 blockade are increased liver enzyme levels and pneumonitis, which
can cause shortness of breath and coughing.

Targeted therapy

Therapies targeted to specific gene mutations also show promise against
melanoma. BRAF mutations, for example, are present in nearly 50% of
melanomas. Two inhibitors of the BRAF protein have been approved by the
FDA for the treatment of melanoma: vemurafenib (formerly called
PLX4032) was approved for metastatic melanoma in 2011, and dabrafenib
(formerly called GSK2118436) was approved for BRAF-mutant melanoma in
2013. Both inhibitors have clinical response rates of about 50% in
patients with metastatic melanoma and activating BRAF mutations.

Another targeted drug approved in 2013 for BRAF-mutant melanoma,
trametinib, inhibits the MEK kinase that is downstream of and activated
by BRAF in the MAP kinase pathway. In a head-to-head clinical trial,
trametinib demonstrated a significant survival advantage over
chemotherapy in patients who had advanced melanoma and activating BRAF
mutations. Unfortunately, although targeted therapies can have high
response rates, these responses usually do not last. Melanomas treated
with a BRAF inhibitor develop resistance after 5–6 months on average,
and less than 10% of cases reach 12 months without developing drug
resistance. The mechanisms of this resistance, and rational approaches
to overcome it, are becoming clearer through the analysis of resistant
tumor tissue.

Michael Davies, M.D., Ph.D., an associate professor in the Department
of Melanoma Medical Oncology, said, “These findings are leading us to
combinatorial approaches. You can’t just target one mutation—you need
to block multiple targets simultaneously to achieve a maximum and
durable clinical benefit. For example, many of the molecular changes
that cause resistance to the BRAF inhibitors do so by reactivating the
MAP kinase pathway. This finding provided the rationale to combine BRAF
inhibitors with MEK inhibitors in order to block the MAP kinase pathway
in two places.” Indeed, the combination of the BRAF inhibitor
dabrafenib and the MEK inhibitor trametinib demonstrated an impressive
clinical response (≥30% decrease in tumor diameter) rate of 75% and an
initial disease control rate of 100%. Furthermore, the combination
almost doubled the average duration of the clinical responses. After 1
year of treatment, 40% of patients treated with the combination were
alive and still responding to treatment—more than four times the rate
seen in patients treated with a BRAF inhibitor only.

“Ten years ago, we could cure about 5% of patients with advanced melanoma, and now we can achieve very good responses in 20%–25%.”

– Dr. Patrick Hwu

Usually, combining anticancer agents increases toxicities. But
surprisingly, combined treatment with dabrafenib and trametinib was
less toxic than treatment with either drug alone. Each agent alone
frequently causes significant skin toxicities; dabrafenib and other
BRAF inhibitors also cause squamous cell carcinomas of the skin in up
to 25% of patients. Most of these squamous cell carcinomas have
activating RAS mutations. “If your normal skin has RAS-mutant cells
present, the BRAF inhibitor makes those cells grow faster through an
effect called paradoxical activation of the MAP kinase pathway,” Dr.
Davies said. “This effect causes the squamous cell cancers to grow and
is also the reason that the BRAF inhibitors are used only in melanoma
patients with activating BRAF mutations.”

But trametinib and other MEK inhibitors block the MAP kinase pathway in
both the tumor cells and the paradoxically activated normal cells. As a
result of this effect, the rate of the squamous cell carcinomas went
from the 20% in patients treated with dabrafenib alone to less than 5%
in patients treated with dabrafenib and trametinib together. Dr. Davies
added, “This combination even reduces the incidence and severity of
skin rashes.” Despite the beneficial effect on the cutaneous toxicities
of the agents, the combination can have other side effects, including
fever and vision problems.

Targeted therapies are also active in patients with brain metastases,
who are often excluded from clinical trials and whose response rates to
chemotherapy are usually very low. At MD Anderson, in the largest
clinical trial ever conducted for melanoma patients with brain
metastases, around 40% of patients treated with dabrafenib had clinical
responses of their brain tumors. In two more trials opening in the next
few months, patients with BRAF-mutant melanoma and brain metastases
will receive dabrafenib with or without trametinib. One trial will
include only patients whose brain metastases are unresectable, while
the other will include only patients for whom surgical resection of
their brain metastases is planned.

Whether the responses to these new targeted drugs will be durable
remains to be seen. Dr. Davies said, “It’s too early to tell whether
there is a subpopulation of patients with metastatic melanoma who are
being cured by dabrafenib combined with trametinib. We’re waiting to
learn as we get longer follow-up data from these clinical trials.”

Combining approaches

The combination of targeted therapy and immunotherapy has been
hypothesized to have better outcomes than either modality alone. This
idea is based partly on the finding that BRAF inhibitors not only slow
tumor growth and destroy tumor cells but also make melanoma more
recognizable to the immune system. Also, these different modalities may
complement each other. Dr. Patrick Hwu said, “We want to put the best
qualities of targeted therapy and immunotherapy together and hopefully
get high response rates that also last a long time.” These rationales
have led to new clinical trials that combine BRAF inhibitors with
immunotherapies such as high-dose bolus IL-2, ipilimumab, and
anti–PD-L1.

“[W]e are in the middle of a transformative era in the development of treatments for patients with metastatic melanoma.”

– Dr. Michael Davies

In another approach, T cells are both stimulated and proliferated using
IL-2 plus a procedure called adoptive T cell transfer. Dr. Patrick Hwu
said, “We take the T cells that are in the tumor and are trying but
failing to kill it, and we proliferate them to large
numbers—billions—outside the body and then reinfuse them into the body
in combination with IL-2. We’ve treated about 80 patients with
metastatic melanoma now, and about half of them have responded well to
it. And importantly, a lot of those responses are durable—for some of
those patients, 5 years out, all of their disease is gone.” To qualify
for adoptive T cell transfer plus IL-2, patients must have CD8-positive
T cells that are highly reactive and tumor specific, a tumor that can
be surgically accessed, and the ability to tolerate high-dose IL-2.
Adoptive T cell transfer is also being tested in combination with T
cell–boosting vaccines and with immune checkpoint blockades in ongoing
trials.

“In the end, I think we need to put these treatment modalities
together,” Dr. Hwu said. “But we have to do so in a way that’s not
toxic, and we also need to make sure that they don’t negate each
other—for example, some targeted therapies might hurt the immune
system. We have to figure out how to combine and sequence these
approaches in a way that will give patients the best opportunity for
long-term survival.”

Dr. Davies agreed that implementing these advances to the best possible
effect will require further calculation. “It’s clear that we are in the
middle of a transformative era in the development of treatments for
patients with metastatic melanoma. While we have made a lot of
progress, there is still a lot of work to do to meet the full potential
of the advances that have been made over the past several years.”

For more
information, contact Dr. Michael Davies at 713-792-3454, Dr. Patrick Hwu at 713-563-1728, or Dr. Wen-Jen Hwu at 713-792-2921.